Benzylcyano-amides

ABSTRACT

Benzylcyano-acids and amides useful as intermediates in the preparation of pharmaceutically valuable 2,4-diamino-5-benzyl pyrimidines.

United States Patent Nussim et al.

[ BENZYLCYANO-AMIDES [75] inventors: Manasse Nussim, Netzmyu'. Ezra Levy, PetabTikvu; Jacob Naiman, Netanyu all of Israel [73] Assignee: Planlex, Ltd., Netzinya, Israel [22] Filed: Nov. 27, 1972 [21] Appl. No: 309,758

[52] U.S. Cl. .i 260/465 D; 260/2564 C [Si] Int. Cl? C07C 121/75 [58] Field of Search 260/465 D (561 References Cited UNITED STATES PATENTS 1462.475 EH96) Strobe] et al. 260/465 167L564 6/1972 Cresswell el 21] r i i 260/465 1676482 7/1 72 Hinkley et all 7. 260/465 X Oct. 7, 1975 OTHER PUBLICATIONS Primary ExaminerLewis Gotts Assistant ExaminerDolph H. Torrence Attorney, Agent, or Firm-Hubbell, Cohen, and Stiefel [57] ABSTRACT Benzylcyano-acids and amides useful as intermediates in the preparation of pharmaceutically valuable 2,4- diamino-S-benzyl pyrimidines.

1 Claim, N0 Drawings BENZYLC "AND-AMI DES The present invention relates to benzylcyano-acids and amides of general formula I wherein R, and R are each selected from among the group consisting of hydrogen. halogen, lower alkyl and lower alkox y. R,-, and R are each a lower alkoxy group.

Y is selected from the group consisting of hydroxy, and

- CHO in which R R R and R... are as defined above is reacted in the presence of a suitable basic catalyst with a compound of general formula III in which Y is as defined above to yield a compound of general formula IV in which R,. R R R and Y are as defined above; and, if desired.

b. the compound of general formula [V is hydrogenated catalytically with a suitable catalyst in a suitable inert solvent to yield the desired compound of general formula V \coY 3 5 in which R,, R R;,, R. and Y are as defined above. The

basic catalyst used in the first reaction step is preferably a secondary amine e.g., piperidine, a metal alkoxide or sodium or potassium hydroxide. This step is performed in an inert solvent such as an alcohol e.g.. methanol, ethanol, isopropanol; ethers, e.g., dioxane. tetrahydrofuran; pyridine water. Said step is preferably performed at elevated temperatures, e.g. between 4080. (All temperatures indicated herein are in degrees centi- 5 grade).

As preferred catalysts for the hydrogenation step there may be mentioned, e.g. palladized or platinized charcoal. As suitable solvents there may be mentioned ethyl acetate; alcohols, e.g. methanol, ethanol, isopropanel. ethers, e.g. dioxane; etc.

The present invention also relates to a process for the preparation of 2,4-diamino-5-benzyl-6-hydroxypyrimidines in which a compound of general formula V is. without a solvent or in the presence of a suitable solvent. reacted with guanidine to yield a compound of general formula VI in which R., R R and R, are as defined above.

The condensation with guanidine, when being performed in an inert solvent, is performed preferably in an alcohol such as methanol. ethanol, isopropanol. etc.

The invention will now be illustrated with reference to the following examples without, however, being limited thereto.

EXAMPLE 1 A mixture of l()() g of 3,4,5-trimethoxy-benzaldehyde and 43.5g of cyanoacetic acid in 1 liter of water containing 2| g of sodium hydroxide was stirred for 2 hours at 50. The clear solution that was thereby obtained was cooled, l2() cc of 5 N hydrochloric acid were 5 added and after additional cooling resulting the precipitate was filtered off and washed with 200 cc of water.

The crude material was dried at and used in the hydrogenation step without further purification. lt melted at 22I224. The yield of a-cyano-3.4,5-trimethoxycinnamic acid was I26 g (94% EXAMPLE 2 I g of a-cyano-3.4.S-trimethoxy-cinnamic acid ohtained as in Example I were dissolved in a solution of If) g of sodium hydroxide in I liter of water and then 7.5 g of of palladizcd charcoal were added. The mixture was hydrogenated at atmospheric pressure until the absorption of hydrogen had stopped. The catalyst was removed and l 75 cc of l()'/( hydrochloric acid were added. The resulting precipitate was filtered off, washed with 200 cc of water and dried in vacuo at 50 for I0 hours to yield 93.l g (93%) of a-cyano-3.4,5.- trimethoxy -dihydrocinnamic acid; m.p. l02l05. A pure sample, recrystallized from chloroform melted at I04l05.

EXAMPLE 3 I00 g of 3.4,5-trimethoxy-benzaldehyde and 44 g of a-cyano-acetamide were dissolved in 300 cc of dry pyridine at 50. To this solution [0 cc of piperidine were added and the mixture was heated at 50 with stirring for 2 hours. The reaction mixture was cooled at room temperature, filtered off and the precipitate was washed on the filter with 50cc of cold isopropanol. The product was dried at 80 to yield l23.6g( 92.5%) of a-cyano-3.4.S-trimethoxy-cinnamamide; m.p. l92-l94. This product was used for the hydrogenation step without further purification. A pure sample, recrystallized from isopropanol. melted at l93l95.

EXAMPLE 4 I00 g of oz-cyano-3,4.S-trimethoxy-cinnamamidc obtained as in Example 3 were dissolved in I liter ofa 9:1 mixture of dioxane-water and 7.5 g of 5% of palladized charcoal were added. The mixture was hydrogenated at atmospheric pressure until the absorption of hydrogen had stopped. The catalyst was removed and the solvent was evaporated under vacuum. The residue was crystallized from ethyl acetate to obtain, after drying at 60 for 0 hours, 89.2 g (89%) of a-cyano- 3.4.5- trimethoxy-dihydrocinnamamide; m.p. I 28 l 30.

EXAMPLE 5 To a solution of 23 g of sodium in I liter of dry methanol, 90 g of guanidine carbonate were added and the mixture was stirred for I5 minutes at room temperature. The precipitated sodium carbonate was filtered off with suction over cellite and the solids were washed with 200 cc of methanol. To this guanidine solution in methanol were added I32 g of a-cyano-3, 4,5- trimethoxy-dihydrocinnamamide prepared as described in example 4. The solution was refluxed for 6 hours and the methanol was distilled off in vacuo. The residue was dissolved in 300 cc of water and the product precipitated by the addition of 6N hydrochloric acid to pH 6. After allowing the product to cool at 0 for 2 hours the white solid was filtered off and washed with 40 cc of ice-cold water. The product was dried at H0l5mm for 12 hours to yield 136.5 g (89)? of colorless 2,4-diamino-5-[ 3', 4'. 5'-trimethoxy-benzyl) -6- hydroxy-pyrimidine; m.p. 275276.

EXAMPLE 6 A mixture of I00 g of a-cyano-3.4,5-trimethoxydihydrocinnamamide and 60 g of freshly prepared guanidine was heated at M0 for I hour with occasional stirring. The reaction mixture was dissolved in cc of hot water and the solution was filtered. The product was precipitated by adding to the clear filtrate, 6N hydrochloric acid to pH 6. After allowing to cool at 0 for 4 hours. the solid was filtered off and washed with 30 cc of ice-cold water. The product was dried at l5mm for l2 hours to obtain [06.7 g (92%) of a compound (m.p. 274276), which was identical with the compound obtained in example '5. I

EXAMPLE 7 This example was carried out exactly as described in example 3 except that 84.7 g of 3,4-dimethoxybem zaldehyde were used in place of the trimethoxybenzaldehyde. The product was dried at 80. to obtain l l l.2 g (94%) of a-cyano -3', 4', -dimethoxycinnamamide; m.p. l82l85. This product was used for the hydrogenation step without further purification. A pure sample, recrystallized from dimethyl formamide had a m.p. of I84l85.

EXAMPLE 8.

The hydrogenation of I00 g of a-cyano -3,4-dimethoxy-cinnamamide was carried out as described in Example 4. Crystallization of the product from dry ethanol yielded g (90%) of oz-cyano- 3.4-dimethoxydihydrocinnamamidc; m.p. l70-I 71.

EXAMPLE 9 This example was run exactly as described in example 5 except that 50 g of the product of Example 8, 10 g of sodium and 38.5 g. of guanidine carbonate in 0.5 liter of dry methanol were used. The crystalline product 2,4 diamino 5- (3'4'-dimethoxybenzyl) -6- hydroxy-pyrimidine, m.p. 268270 weighed 52 g (87.5%)

EXAMPLE I0 This example was carried out exactly as described in Example 6, except that I00 g of the product of example 8 and 70 g of freshly prepared guanidine were used. The product obtained 2,4-diamino -5- (3',4'-dimethoxybenzyl )-6-hydroxy pyrimidine m.p. 268270 weighed I08 g. (91%).

We claim: 1. a-cyano-3,4,5-trimethoxy-dihydrocinnamamide.

qg gy UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent NO. Dated October 7, Inventor g et 81 It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 2, line 65: "resulting the" should read the resulting Signed and Scaled this third Day Of February 1976 [SEAL] Arrest."

RUTH C. MRSON C. MARSHALL DANN Arresting Officer Commissioner uj'Parems and Trademarks 

1. A-CYANO-3,4,5-TRIMETHOXY-DIHYDROCINNAMAMIDE. 